Novel enteric combination therapy

ABSTRACT

There is disclosed herein a composition for treating gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux esophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson&#39;s disease, MS, Alzheimer&#39;s Disease, Motor Neuron Disease or autism, the composition comprising: (i) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (ii) at least one anti-clostridial agent selected from the above combined with an opioid blocking agent. There is also disclosed herein a method of treating various gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson&#39;s disease, MS, Alzheimer&#39;s Disease, Motor Neuron Disease or autism, the method comprising administering orally, via enema or by suppository: (i) a composition of the invention; (ii) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (iii) at least one anti-clostridial agent selected from the above and an opioid blocking agent to a patient in need of such treatment.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/799,680, filed Feb. 24, 2020, now pending, which is a continuation ofU.S. Ser. No. 16/725,988, filed Dec. 23, 2019, now pending, which is acontinuation of U.S. Ser. No. 15/794,819, filed Oct. 26, 2017, now U.S.Pat. No. 10,517,922, issued Dec. 31, 2019, which is a continuation ofU.S. Ser. No. 15/276,342, filed Sep. 26, 2016, now abandoned, which is acontinuation of U.S. Ser. No. 14/807,804, filed Jul. 23, 2015, now U.S.Pat. No. 9,468,663, which is a continuation of U.S. Ser. No. 14/324,924,filed Jul. 7, 2014, now U.S. Pat. No. 9,095,545, issued Aug. 4, 2015,which is a continuation of U.S. Ser. No. 13/499,270, filed Apr. 25,2012, now U.S. Pat. No. 8,772,242, issued Jul. 8 2014, which is anational phase patent utility filing under 35 USC § 371, forInternational (PCT) Patent Application serial no. PCT/AU2010/001410,filed Oct. 22, 2010, which claims benefit of priority to AustralianPatent Application Serial No. 2009905229, filed Oct. 26, 2009. Theaforementioned applications are expressly incorporated by referenceherein in their entirety for all purposes.

TECHNICAL FIELD

The present invention relates generally to the field of pharmaceuticalcompositions. More specifically the present invention relates to thepharmaceutical composition for treating gastrointestinal disorders anduses thereof.

BACKGROUND OF THE INVENTION Bowel Flora

The human bowel flora is complex and is composed of around 24,000bacterial subspecies. It is considered to be a ‘virtual organ’ and ispoorly understood because no more than approximately 15%-20% of thebacterial types have ever been cultured. Indeed, there is a real needamong medical practitioners to better understand the concept of bowelflora being a ‘virtual organ’ which is abnormal or infected for example.Bowel flora can be infected either as an acute infection where theinfecting agent can be bacteria, viruses or parasites. The flora canalso be infected for a prolonged period i.e. a chronic infection e.g. C.difficile, Giardia lamblia, Giardia Blastocystis hominis, Aeromonas orother pathogens. In this invention the concept of a chronic bowel florainfection will be expanded and addressed. It should also be noted thatin spite of knowing some acute and chronic infective agents theoverwhelming majority of agents infecting the bowel flora are yet to bedescribed and discovered.

Constipation

Constipation according to the view taken in this patent application isone such infective disorder of the virtual organ—the bowel flora. It isconsidered to be an infection by a bacterium or bacterial speciescapable of producing bioactive substances which affect the bowel walland the body in general. In contrast to the present view of thisinventor, many theories have been put forward as to the cause ofconstipation. In the past numerous publications have avoided dealingwith a cause of constipation and addressed associations rather thancausality. Causality has at times been discussed but has been ascribedto differences in diet, psychological causes, motility disturbances,enteric nervous dysplasia and others. Although there are many secondarycauses of constipation such as hypothyroidism and various medications,the most common cause of constipation remains obscure. Indeed, patientsand doctors remain baffled by the fact that the common variety everydayconstipated patient generally eats an average amount or an excessiveamount of fibre, drinks enough water and has an average exerciseprogramme—and yet remains constipated—sometimes for days on end. It isalso known that taking fibre away from normal people does not cause themto be constipated. Hence, there is a discrepancy between our ideas orbeliefs and the real cause of constipation.

Looking at past therapies, constipation has been treated by methodswhich have often been found by chance, trial and error, or as a sideeffect of a novel therapy. Mild constipation will respond to change indiet, increase in fibre intake and various laxatives including senna,coloxyl, teas and osmotic laxatives such as lactulose, sorbitol,mannitol and PEG 3550. Various other laxatives have been describedincluding colchicine, bisacodyl, castor oil, linactolide andprucalopride. Methyl naltrexone and naloxone have also been used inopiate-induced constipation. Probiotics have been used empirically andserotonin receptor agonists including tagaserod have been used.Cisapride, metoclopromide, mosapride and domperidone have been shown toincrease motility in some patients.

However, no current literature refers to constipation as being apossible infection of gut flora with a particular set of bacterialagents that would be mediating constipation via bioactive substancesproduced by these bacteria. Although some antibiotics have been listedin literature as affecting bowel activity when used in constipationincluding neomycin, clarithromycin, metronidazole and rifaximin theresults have been variable and not reproducible [Brandt L J et al AmerJournal Gast 2009; 104(Suppl): S8-S35.]

Overall then, previous and current medications being developed for thetreatment of constipation appear to be dealing with mechanisms that donot address the underlying mechanism of constipation as described inthis patent application. Furthermore, some systemic and neurologicconditions are associated with constipation and other bowel disorderswhich in part may be causally related, for example Parkinson's disease,MS, Alzheimer's Disease, Motor Neuron Disease (also known as ALS),autism and other neurologic disorders.

OBJECT OF THE INVENTION

It is an object of the present invention to overcome or substantiallyameliorate at least one of the above disadvantages or to provide asuitable alternative.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided acomposition for treating gastrointestinal or neurological disorders,constipation, functional constipation, irritable bowel syndrome,diverticulitis, travelers diarrhoea, chronic idiopathic nausea,IBD-associated constipation and diarrhoea, pseudo-obstruction, diabeticgastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy,flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax,Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease orautism, the composition comprising:

(i) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(ii) at least one anti-clostridial agent selected from the abovecombined with an opioid blocking agent.

According to a second aspect of the present invention, there is provideda method of treating various gastrointestinal or neurological disorders,constipation, functional constipation, irritable bowel syndrome,diverticulitis, travelers diarrhoea, chronic idiopathic nausea,IBD-associated constipation and diarrhoea, pseudo-obstruction, diabeticgastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy,flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax,Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease orautism, the method comprising administering orally, via enema or bysuppository:

(i) a composition of the invention;

(ii) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(iii) at least one anti-clostridial agent selected from the above and anopioid blocking agent to a patient in need of such treatment.

In one embodiment, the agents are administered simultaneously orconsecutively in any order.

According to a third aspect of the present invention there is provideduse of:

(i) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(ii) at least one anti-clostridial agent selected from the abovecombined with an opioid blocking agent in the manufacture of amedicament for treating various gastrointestinal or neurologicaldisorders, constipation, functional constipation, irritable bowelsyndrome, diverticulitis, travelers diarrhoea, chronic idiopathicnausea, IBD-associated constipation and diarrhoea, pseudo-obstruction,diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autismenteropathy, flatulence, halitosis, chronic fatigue, bloating,proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, MotorNeuron Disease or autism.

According to a fourth aspect of the present invention there is provideduse of at least one anti-clostridial agent selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid;

combined with an antiopioid blocking agent in opioid-inducedconstipation.

Definitions

The following definitions are intended as general definitions and shouldin no way limit the scope of the present invention to those terms alone,but are put forth for a better understanding of the followingdescription.

Unless the context requires otherwise or specifically stated to thecontrary, integers, steps, or elements of the invention recited hereinas singular integers, steps or elements clearly encompass both singularand plural forms of the recited integers, steps or elements.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers, but not the exclusionof any other step or element or integer or group of elements orintegers. Thus, in the context of this specification, the term“comprising” means “including principally, but not necessarily solely”.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of said steps or features.

All the references cited in this application are specificallyincorporated by reference are incorporated herein in their entirety.Inclusion herein of any given reference is not intended to indicate thatthe reference is generally known in Australia or elsewhere.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

There is disclosed herein a composition for treating gastrointestinal orneurological disorders, constipation, functional constipation, irritablebowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathicnausea, IBD-associated constipation and diarrhoea, pseudo-obstruction,diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autismenteropathy, flatulence, halitosis, chronic fatigue, bloating,proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, MotorNeuron Disease or autism, the composition comprising:

(i) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(ii) at least one anti-clostridial agent selected from the abovecombined with an opioid blocking agent.

As required, the composition may include a pharmaceutically acceptablecarrier.

In one embodiment the vancomycin derivative is carbohydrate-modifiedvancomycin, vancomycin-disulfide derivative, lipidated vancomycin,chlorobiphenyl-desleucyl-vancomycin, oritavancin, telavancin, orchlorobiphenyl vancomycin.

In one embodiment the aminoglycoside is selected from the groupconsisting of streptomycin, neomycin, framycetin, paromomycin,ribostamycin, kanamycin, amikacin, arbekacin, beanamycin, dibekacin,tobramycin, spectinomycin, hygromycin B, paromomycin sulfate,streptomycin, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin,astromicin and mixtures thereof.

In one embodiment the nitroimidazole is selected from the groupconsisting of metronidazole, tinidazole, nimorazole, secnidazole,ordinazole and mixtures thereof.

In one embodiment the ansamycin is selected from the group consisting ofrifaximin, rifampicin, rifabutin, rifapentine and mixtures thereof.

In one embodiment the prokinetic agents are selected from the groupconsisting of tegaserod, domperidone, metoclopramide, mosapride,erythromycin and mixtures thereof.

In one embodiment the 5-aminosalicylic acid is selected from mesalazine,olsalazine, balsalazide and mixtures thereof.

In one embodiment the antiopioid blocking agent is selected from methylnaltrexone or naloxone hydrochloride.

In one embodiment the composition includes the combination of vancomycinand metronidazole.

In another embodiment the composition includes the combination ofvancomycin and rifaximin.

In one embodiment the composition includes the combination of rifaximinand prucalopride.

In one embodiment the composition includes the combination rifaximin,metronidazole and colchicine.

In one embodiment the composition includes the combination vancomycin,metronidazole and colchicine.

In one embodiment the composition incudes the combination vancomycin,aminoglycoside and colchicine.

In one embodiment the composition includes the combination rifamycin,colchicine and metronidazole.

In one embodiment the composition includes the combination vancomycintogether with a prokinetic agent.

In one embodiment the composition includes the combination vancomycin,olsalazine and colchicine.

In one embodiment the composition includes the combination of vancomycinand methyl naltrexone or naloxone hydrochloride.

In one embodiment the composition includes the combination of naloxonehydrochloride, vancomycin and metronidazole.

In on embodiment the composition includes the combination of naloxonehydrochloride and colchicines.

In one embodiment the composition includes the combination of naloxonehydrochloride, vancomycin, and rifaximin.

In one embodiment the composition includes the use of naloxonehydrochloride and rifaximin.

In another embodiment, the present invention relates to a method oftreating various gastrointestinal or neurological disorders,constipation, functional constipation, irritable bowel syndrome,diverticulitis, travelers diarrhoea, chronic idiopathic nausea,IBD-associated constipation and diarrhoea, pseudo-obstruction, diabeticgastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathyflatulence, halitosis, chronic fatigue, bloating, proctalgia fugax,Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease orautism, the method comprising administering orally, via enema or bysuppository;

(i) a composition of the invention;

(ii) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(iii) at least one anti-clostridial agent selected from the above and anopioid blocking agent to a patient in need of such treatment

In one embodiment the agent is administered in doses ranging from 50 mgper day to 500 mg per day.

In one embodiment when present, the colchicine is administered in dosesof 0.005 mg to 5 mg per day and the 5-aminosalicylic acid isadministered in doses of 100 mg to 3 gm per day.

In various embodiments, the agents are administered simultaneously suchas in the form of a single composition of the invention or areadministered separately in any order. In various embodiments, the agentsadministered may be those listed above as combinations. For example, thecombination of vancomycin and metronidazole; the combination ofvancomycin and rifaximin; the combination of rifaximin and prucalopride;the combination rifaximin, metronidazole and colchicine, the combinationvancomycin, metronidazole and colchicine; the combination vancomycin,aminoglycoside and colchicine; the combination rifamycin, colchicine andmetronidazole; the combination vancomycin together with a prokineticagent; the combination vancomycin, olsalazine and colchicine; thecombination of vancomycin and methyl naltrexone or naloxonehydrochloride, the combination of naloxone hydrochloride, vancomycin andmetronidazole; the combination of naloxone hydrochloride andcolchicines; the combination of naloxone hydrochloride, vancomycin, andrifaximin; or the combination of naloxone hydrochloride and rifaximin

In another embodiment, the present invention relates to use of:

(i) at least two anti-clostridial agents selected from the groupconsisting of:

vancomycin, vancomycin derivatives, a multi-valent polymer ofvancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide,colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or

(ii) at least one anti-clostridial agent selected from the abovecombined with an opioid blocking agent.

in the manufacture of a medicament for treating various gastrointestinalor neurological disorders, constipation, functional constipation,irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronicidiopathic nausea, IBD-associated constipation and diarrhoea,pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, refluxesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue,bloating, proctalgia fugax, Parkinson's disease, MS, Alzheimer'sDisease, Motor Neuron Disease or autism.

The description of the invention is tied to the description of thecausality. Mentioned above is the concept of the bowel flora being avirtual organ, consisting largely of various bacteria most of which arenot known to mankind. A number of clinical observations have led theinventor to this conceptualisation of the mechanisms which have led tothe invention. Firstly when patients with constipation take multipleantibiotics e.g. for treatment of Helicobacter pylori infection, it wasnoticed their constipation resolves and remains much better for severaldays even after they stop the antibiotics, suggestine that constipationis mediated by an infection of the bowel flora which was suppressed bythe antibiotics. Furthermore, the use of vancomycin alone has beenpreviously described in constipation and these points to constipationbeing caused by a Clostridial infection (Andrews et al Euro J Gast Hep1992; 4:245-7, and Celik A F et al, Alimentary Pharmacol and Ther, 1995;9:63-68). However, the inventor recognised that the use of vancomycinalone is inefficient and requires an improvement because not allpatients respond and respond but partially to be clinically effective.Nevertheless, such an observation has strongly pointed to bowel floraabnormality or bowel flora infection as the primary cause of most casesidiopathic constipation. The inventor's belief that the etiology ofconstipation being infection was further strengthened by the use of‘faecal bacteriotherapy’ i.e., when transplantation of bowel flora wasshown to reverse constipation (T J Borody et al J Clin Gastroenterol2004; 38:475-483). The implantation of new bacteria from a healthy donorhas been definitively shown to produce prolonged reversal ofconstipation in the occasional patients treated (Andrews P J et alEuropean Gastroenterology and Hepatology 1992; 4:245-247).

Hence the mechanism of the abnormality appears to be an infective oneand probably similar to that of Clostridium botulinum which also causessevere constipation as one of its first symptoms in babies infected withthis agent. It is likely that such Clostridia release neuro-activeopioid-like substances which then paralyse the bowel's motor activity(peristalsis) which is in effect, the mechanism for constipation in mostpatients. Such bacterial substances enter the circulation and may alsoparalyse the small bowel, so causing accumulation of gas in the smallbowel which clinically presents as bloating. Such circulating substancesare likely also to reduce gastric emptying by partial paralysis [slowgastric emptying] and by relaxing the tone of the lower oesophagealsphincter causing reflux oesophagitis—the mechanism of oeosophagitisknown to be frequently associated with constipation. Blockade of theseneuro-active opioid-like substances by their antagonists would betherefore expected to further help resolve the dysmotility of the colon,small bowel, stomach and oesophagus. These would include methylnaltrexone and naloxone hydrochloride in doses ranging from 0.01 mg to1000 mg per day.

Hence, the appropriate approach to the treatment of constipation wouldbe to treat the causal infective agent or agents, even though they maynot be able to be cultured and block the opioid neuropeptides theysecrete.

Given the background given above and the results from the treatment ofnumerous patients, the invention constitutes an antimicrobialcombination therapy that would pass down the bowel and suppress oreradicate the culprit infective agent or agents and in somecircumstances opioid blockers to make the treatment more effective.Various agents are capable of inhibiting Clostridia and cause laxation.The foremost of these is vancomycin or vancomycin derivative when usedorally as it is mostly not absorbed by the gut. The antimicrobial agentsinclude vancomycin, a multi-valent polymer of vancomycin,aminoglycosides including streptomycin, neomycin, framycetin,paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, beanamycin,dibekacin, tobramycin, spectinomycin, hygromycin B, paromomycin sulfate,streptomycin, gentamicin, netilmicin, sisomicin, isepamicin, verdamicinand astromicin. Other anti-infective agents that can be used includenitroimidazoles such as metronidazole, tinidazole, nimorazole,secnidazole and ordinazole. Another group of agents that is active isrifaximin, a semi synthetic rifamicin based agent from a larger familyof Ansamycin's which includes rifampicin and rifabutin as well asrifapentine. Rifaximin is preferable because it is not absorbed from theintestine. Another useful agent to be in combination with thosementioned includes nifuroxazide—another non-absorbed product. Variousmedications which can increase water secretion in the bowel such ascolchicine and prucalopride can also be effectively combined. Opioidblocking agents include methyl naltrexone and naloxone hydrochloride.

The pharmacological combinations that have been found to be usefulinclude a composition of two or more anti-clostridial alone oranti-clostridial agents combined with other medications enumerated. Theinvention describes compositions and use thereof for the manufacture ofa medication for the treatment of constipation andconstipation-associated conditions. The best disclosed compositionsinclude that of vancomycin and metronidazole, vancomycin and rifaximin,vancomycin and naloxone hydrochloride and rifaximin and naloxonehydrochloride. These can be taken orally in doses of these medicationsranging from 0.01 mg per day through to 5000 mg per day. The combinationcan be taken as the currently available capsules and tablets in singleor divided dosing regimens. Another and preferable combination is thatof a capsule or tablet which is enteric coated so that it opens in thedistal small bowel or the large bowel so reducing any absorption ofabsorbable drugs e.g. metronidazole. The medication can be taken longterm to suppress the Clostridial super-infection of the bowel florawhich so helps to increase gut motility. Other combinations includerifaximin and prucalopride in same covered dose ranges in single ordivided doses, rifaximin, metronidazole and colchicine, and vancomycin,metronidazole and colchicine—colchicine in doses of 0.005 mg-5 mg perday. This combination can also be as an enteric-coated product to limitabsorption. A combination of vancomycin, aminoglycosides and colchicineis yet another composition. Rifamycin, colchicine and metronidazole isyet another combination.

A further set of agents which can be added to single antibiotics orcombined antibiotics include prokinetic agents such as tegaserod,domperidone, metoclopramide, mosapride, erythromycin and5-aminosalicylic acid products which also inhibit Clostridia includingmesalazine, olsalazine and balsalazide. In respect to these, one couldcombine vancomycin with olsalazine—the latter 100 mg-3 gm per day, orvancomycin with any other prokinetic agent used in accepted appropriatedoses. In a further combination the use of vancomycin, olsalazine andcolchicine can be combined. In fact any of the groups above can becombined in two or more combinations to control the constipation ofbacterial infection.

Apart from describing the various compositions useful in the treatmentof various gastrointestinal disorders, it should be mentioned that anumber of often disparate disorders have been noticed to respond well tothese combinations, indicating a microbiologic etiology of suchdisorders. These include constipation, functional constipation,irritable bowel syndrome, diverticulitis, traveler's diarrhoea, chronicidiopathic nausea, IBD-associated constipation and diarrhoea,pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, refluxoesophagitis, autism enteropathy, flatulence, halitosis, chronicfatigue, bloating and proctalgia fugax and in the above neurologicaldisorders.

The invention will now be described with reference to the followingexamples which should not be construed as limiting on the invention.

EXAMPLES Example 1

A 38 year old female patient with life-long constipation, defecatingbetween 0-2 times per week, had multiple investigations carried out andno abnormalities were found with respect to the colon or the bowelflora, and had failed known standard therapies. She was not hypothyroidand had otherwise normal blood tests. She was given a trial ofVancomycin 500 mg bd and Metronidazole 200 mg bd and began defecating byday 3 of the treatment. She was able to continue defecating normallywith her constipation completely being reversed while she took thetherapy for 4 weeks. After stopping the therapy, within 2 weeks theconstipation started recurring. Restarting the treatment again allowedher to defecate normally. Apart from the constipation her bloating wasmarkedly reduced during treatment, and her sensation of ‘fullness’ wasimproved and her reflux symptoms also lessened. Her previous tirednesswas markedly reduced during treatment.

Example 2

An elderly gentleman with severe constipation requiring 6 coloxyltablets per day and Parkinson's disease was commenced on Vancomycin 500mg bd, Metronidazole 400 mg bd and Colchicine 0.5 mg bd. Within 3 dayshe was defecating normally and was able to stop taking the Coloxyl.Unexpectedly, by week 4 his Parkinson's disease had improved quitedramatically. In spite of still-continuing to take Sinemet in hisoriginal dose, he no longer experiences any tremor and over the periodof several months his gait improved and ‘Glabellar tap’ test reversed tonormality. Continuing the treatment for over a year—his constipationremained completely gone, his Parkinson's was virtually undetectable andhe was able to reduce his dose of Sinemet, suggesting his Parkinson'sdisease neurotoxicity may have originated from the bowel flora.

Example 3

A 41 year old female with a 10 year constipation history associatedbloating, tiredness and headaches was commenced on 500 mg of Vancomycintwice daily and Rifaximin 200 mg twice daily. After a week's treatmenther constipation improved markedly but the Rifaximin had to be increasedto 400 mg twice daily for the constipation and other symptoms to bevirtually completely undetectable. Progressively her bloating improvedand her tiredness and headaches improved. She continued on treatment nowfor over 3 months and continues well on the therapy not wanting to stopthe treatment because she feels so well.

Example 4

An 8 year old male with constipation alternating at times with diarrheawith Autism Spectrum Disorder was commenced on Vancomycin 250 mg twicedaily together with Naloxone hydrochloride 10 mg twice daily. After 3weeks of treatment the constipation was completely resolved but inaddition his behavior and lethargy changed. He became affectionate andrelatively calm, achieving toilet retraining which he had neverpreviously achieved. His vocabulary began to increase quite rapidly, hison task performance, compliance with parental requests and awareness ofsurroundings improved quite quickly and he was engaging in positiveactivities. Repetitive and self stimulatory behaviors were reduced. Theimprovement lasted for the duration of four months treatment as variousparameters kept on improving.

Example 5

Elderly male with severe constipation, bloating and abdominal pain andearly Parkinson's disease characterized by stiffness was commenced onVancomycin 500 mg twice daily together with Rifaximin 500 mg twice dailyand Naloxone hydrochloride 10 mg twice daily. Within a week he wasdefecating normally. I was able to stop the various teas and Normacoltogether with Movicol which he was using for constipation. By week 6 hisstiffness had markedly improved, he had stopped “freezing” whileattempting to initiate walking and his fine tremor, previously present,was no longer detectable. Cogwheel rigidity also improved and he wasable to reduce his anti-Parkinsonian treatment by about 30% at thisstage. He continued the treatment for 6 months and his Parkinsoniansymptoms further regressed although they were not completelyundetectable at this stage.

Example 6

A 52 year old female with lifelong constipation associated with markedbloating was commenced on 500 mg Vancomycin twice daily, 500 mgRifaximin twice daily and Naloxone hydrochloride 10 mg twice daily.After one week of treatment her constipation improved markedly and kepton improving over the next 2-3 weeks. Her bloating took some time toresolve and about 5 weeks she was not able to detect bloating eventhough she may have eaten a fatty meal. She continued on therapy for 6months without changing and she was asymptomatic at that time.

Although the invention has been described with reference to specificexamples, it will be appreciated to those skilled in the art that theinvention may be embodiment in many other forms.

1: A therapeutic composition comprising: (i) vancomycin, a vancomycinderivative, a multi-valent polymer of vancomycin, or a combinationthereof wherein the vancomycin derivative comprises acarbohydrate-modified vancomycin, a vancomycin-disulfide derivative, alipidated vancomycin, a chlorobiphenyl-desleucyl-vancomycin orchlorobiphenyl vancomycin; and (ii) rifaximin.
 2. (canceled) 3: Thetherapeutic composition of claim 1, further comprising anaminoglycoside, wherein optionally the aminoglycoside is selected fromthe group consisting of streptomycin, neomycin, framycetin, paromomycin,ribostamycin, kanamycin, amikacin, arbekacin, beanamycin, dibekacin,tobramycin, spectinomycin, hygromycin B, paromomycin sulfate,streptomycin, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin,astromicin and mixtures thereof. 4: The therapeutic composition of claim1, further comprising a nitroimidazole, wherein optionally thenitroimidazole is selected from the group consisting of metronidazole,tinidazole, nimorazole, secnidazole, ordinazole and mixtures thereof. 5:The therapeutic composition of claim 1, further comprising an ansamycin,wherein optionally the ansamycin is selected from the group consistingof rifampicin, rifabutin, rifapentine and mixtures thereof. 6: Thetherapeutic composition of claim 1, further comprising a prokineticagent, wherein optionally the prokinetic agent is selected from thegroup consisting of tegaserod, domperidone, metoclopramide, mosapride,erythromycin and mixtures thereof. 7: The therapeutic composition ofclaim 1, further comprising a 5-aminosalicylic acid, wherein optionallythe 5-aminosalicylic acid is selected from the group consisting ofmesalazine, olsalazine, balsalazide and mixtures thereof. 8: Thetherapeutic composition of claim 1, further comprising an anti-opioidblocking agent, wherein optionally the anti-opioid blocking agent isselected from the group consisting of methyl naltrexone, naloxonehydrochloride and a combination thereof. 9: The therapeutic compositionof claim 1, further comprising metronidazole.
 10. (canceled) 11: Thetherapeutic composition of claim 1, further comprising prucalopride. 12:The therapeutic composition of claim 1, further comprising metronidazoleand colchicine. 13: The therapeutic composition of claim 1, furthercomprising metronidazole and colchicine. 14: The therapeutic compositionof claim 1, further comprising an aminoglycoside and colchicine. 15: Thetherapeutic composition of claim 1, further comprising rifamycin,colchicine and metronidazole.
 16. (canceled) 17: The therapeuticcomposition of claim 1, further comprising olsalazine and colchicine.18: The therapeutic composition of claim 1, further comprising methylnaltrexone or naloxone hydrochloride. 19: The therapeutic composition ofclaim 1, further comprising naloxone hydrochloride and metronidazole.20: The therapeutic composition of claim 1, further comprising naloxonehydrochloride and colchicine. 21: The therapeutic composition of claim1, further comprising naloxone hydrochloride. 22-27. (canceled) 28: Thetherapeutic composition of claim 1, further comprising apharmaceutically acceptable carrier. 29: A pharmaceutical compositioncomprising: a therapeutic composition of claim 1, and a pharmaceuticallyacceptable carrier.